This invention relates to metallocene compositions containing vanadium (IV). More particularly, the invention relates to Vanadium (IV) complexed metallocene, having spermicidal activity.
The known spermicidal agents, nonoxynol-9 and gramicidin, exert their effects via a detergent-like ability to damage the sperm plasma membrane, perturb its conformation and destroy its semi-permeable nature thereby impairing the sperm motility and egg fertilizing functions (Wilborn, et al., Fertil Steril 1983; 39:717-719; Bourinbaiar, et al., Life Sci 1994; 54:PL 5-9). Because of their non-specific membrane disruptive properties, such vaginal spermicides have been shown to damage the cervicovaginal epithelium, as well, which may lead to a lower degree of protection from sexually transmitted diseases (Niruthisard, et al., Sex Transm Dis 1991; 18:176-179). A novel vaginal contraceptive preferably does not function with the non-specific membrane toxicity mediated by detergent-type action of the currently available vaginal contraceptives.
Vanadium is a physiologically essential element which can be found in one of five (I to V) oxidation states. Several inorganic salts containing vanadium with oxidation state +4 (IV) have been shown to function as modulators of cellular redox potential and to exert pleiotropic effects in multiple biological systems by catalyzing the generation of reactive oxygen intermediates. See, for example, Shi, et al., Ann Clin Lab Sci 1996; 26:390-49; Byczkowski, et al., Bull Environ Contam Toxicol 1988; 41:696-703; Younes, et al., Toxicology 1991; 66:63-74, and Sakurai, et al., Biochem Biophys Res Commun 1995; 206:133-137. Reactive oxygen intermediates have been reported to affect sperm motility by a combination of peroxidation of membrane lipids and proteins (Aitken, et al., Biol Reprod 1989; 40:183-197; Jones, et al., Fertil Steril 1979; 31:531-537). Peroxidative damage to the sperm plasma membrane is an important pathophysiological mechanism in the onset of male infertility (Aitken, et al., BioEssays 1994; 16:259-267). It has also been shown that superoxide radicals generated by the action of xanthine oxidase exert a direct, suppressive effect on many aspects of sperm function (Aitken, et al., J. Reprod. Fertil. 1993; 97:441-450). Sperm are thought to be particularly susceptible to oxidative stress by virtue of their high content of unsaturated fatty acids and their relative paucity of cytoplasmic enzymes for scavenging the reactive oxygen intermediates that initiate lipid peroxidation (Alvarez, et al., J Androl 1987; 8:338-348).
There is a need for new spermicidal compounds for contraceptive purposes. The ability of vanadium IV containing organometallic complexes to catalyze the generation of reactive oxygen species was evaluated for its potential to impact sperm activity. Results of studies with structurally distinct organometallic complexes containing vanadium (IV) surprisingly demonstrated these compounds to be potent spermicidal agents at nano-micromolar concentrations. These compounds have also surprisingly been found to exhibit selective apoptosis-inducing activity against testicular germ cells in vivo.
Organometallic complexes containing vanadium (IV), including vanadocene dichloride (VDC), bis (methylcyclopentadienyl) vanadium dichloride (VMDC), vanadocene dibromide (VDB), vanadocene diiodide (VDI), vanadocene diazide (VDA), vanadocene dicyanide (VDCN), vanadocene dioxycyanate (VDOCN), vanadocene dithiocyanate (VDSCN), vanadocene diselenocyanate (VDSeCN), vanadocene ditriflate (VDT), vanadocene monochloro oxycyanate (VDCO), and vanadocene monochloro acetonitrilo tetrachloro ferrate (VDFE) were found to have spermicidal activity. Specifically, the xe2x80x9cvanadocenexe2x80x9d complexes elicited potent spermicidal activity at nano-micromolar concentrations with an order of efficacy VDSeCN greater than VDSCN greater than VDB greater than VMDC greater than VDA greater than VDC greater than VDI greater than VDT greater than VDFE greater than VDCO. In contrast, control metallocene complexes containing titanium, zirconium, molybdenum, and hafnium lacked spermicidal activity.
Accordingly, the present invention includes a contraceptive composition containing a spermicidal effective amount of an organometallic cyclopentadienyl vanadium IV complex and a pharmaceutically acceptable carrier, diluent or vehicle.
Another aspect of the present invention is a method of contraception including the step of contacting sperm with a spermicidal effective amount of an organometallic cyclopentadienyl vanadium IV complex.
Yet another embodiment of the invention utilizes the selective apoptotic-inducing properties of organometallic cyclopentadienyl vanadium IV complexes against testicular germ cells to selectively kill normal testicular germ cells and testicular germ cell tumors.